Distinct epitopes for anti-glomerular basement membrane Alport alloantibodies and Goodpasture autoantibodies within the noncollagenous domain of α3(IV) collagen: A janus-faced antigen

Xu Ping Wang, Agnes B. Fogo, Selene Colon, Giovanna Giannico, Sameh R. Abul-Ezz, Jeffrey H. Miner, Dorin Bogdan Borza

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Alport posttransplantation anti-glomerular basement membrane (GBM) nephritis is mediated by alloantibodies against the noncollagenous (NC1) domains of the α3α4α5(IV) collagen network, which is present in the GBM of the allograft but absent from Alport kidneys. The specificity of kidney-bound anti-GBM alloantibodies from a patient who had autosomal recessive Alport syndrome (ARAS) and developed posttransplantation nephritis was compared with that of Goodpasture autoantibodies from patients with autoimmune anti-GBM disease. Allograft-eluted alloantibodies reacted specifically with α3α4α5 NC1 hexamers, targeting their α3NC1 and α4NC1 subunits, and recognized a noncontiguous alloepitope formed jointly by the EA and EB regions of α3NC1 domain. In contrast, human Goodpasture autoantibodies recognized the separate EA and E B autoepitopes of α3NC1 but not the composite alloepitope. Molecular modeling of α3NC1 revealed that the alloepitope is more accessible within the NC1 hexamers than the partially sequestered Goodpasture autoepitopes. Overall, the specificity of alloantibodies indicated a selective lack of immune tolerance toward the α3 and α4(IV) collagen chains not expressed in patients with ARAS. Using COL4A3 knockout mice, a model of ARAS, it was shown further that acid-dissociated rather than native α3α4α5 NC1 hexamers elicited murine anti-GBM antibodies most closely resembling human ARAS alloantibodies. In contrast, α3NC1 monomers elicited Goodpasture-like murine antibodies, targeting the EA and EB autoepitopes. Thus, the identity of α3NC1 epitopes targeted by anti-GBM antibodies is strongly influenced by the molecular organization of the immunogen. These findings suggest that different isoforms of α3(IV) collagen may be implicated in the pathogenesis of ARAS posttransplantation anti-GBM nephritis and Goodpasture disease.

Original languageEnglish
Pages (from-to)3563-3571
Number of pages9
JournalJournal of the American Society of Nephrology
Volume16
Issue number12
DOIs
StatePublished - Dec 1 2005

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